KR100887008B1 - Methods of using and compositions comprising dopamine reuptake inhibitors - Google Patents

Abstract

It suggests how to treat and prevent diseases and abnormalities including erectile dysfunction, mood disorder, weight gain or obesity, brain function disorder, pain, obsessive compulsive disorder, drug abuse, chronic disease, anxiety, eating disorder, migraine, incontinence. The method consists of administering dopamine reuptake inhibitors and optionally added pharmacologically active compounds. Also provided are pharmaceutical compositions and dosage forms consisting of dopamine reuptake inhibitors and optionally added pharmacologically active compounds. Suitable dopamine reuptake inhibitors are racemic or optically pure sibutramine metabolites, or pharmaceutically acceptable salts, solvates or clathrates thereof and pharmaceutically acceptable excipients. Suitable additional pharmacologically active compounds include drugs that affect the central nervous system, such as 5-HT ₃ antagonists.

 Dopamine Recombination Inhibitors

Description

Composition consisting of dopamine re-inhibiting inhibitors and methods of using the same {METHODS OF USING AND COMPOSITIONS COMPRISING DOPAMINE REUPTAKE INHIBITORS}

The present invention is U.S. Division Application No. 60 / 097,665 (August 24,1998) and U.S. Division Application No. Claim priority on 60 / 099,306 (September 2, 1998).

1. Field of the Invention

The present invention relates to a composition comprising a dopamine recombination inhibitor, in particular a racemic of sibutramine and an optically pure metabolite and a method of using the same.

2. Background of the Invention

Sibutramine has the chemical name [N-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl] -N-, N-dimethylamine, and is described in US Pat. Neuronal monoamine reuptake inhibitors as disclosed at 4,746,680 and 4,806,570. Sibutramine inhibitors inhibit re-receptiveness of norepinephrine, and to some extent, re - receipt of serotonin and dopamine (Buckett et al., Prog. Neuro-psychopham. & Biol. Psychiat., 12: 575-584, 1998; King et al., J. Clin. Pharm., 26: 607-611 (1989).

Racemic sibutramine is sold as monohydrate hydrochloride under the trade name MERIDIA ^® and is prescribed for the treatment of obesity ( Physician's Desk Reference ^® 1494-1498 (53 ^rd ed., 1999)). Obesity treatment with racemic sibutramine is described in US Patene No. 5,436,272.

Sibutramine has been extensively studied and is reported to be useful for the treatment of various diseases. For example, U.S. Patent No. 4,552,828, 4,746,680, 4,806,570, 4,929,629 provide a method for treating depression with racemic sibutramine, and U.S. Pat. Patent No. 4,871,774 and 4,939,175, respectively, show how racemic sibutramine can be used to treat Parkinson's disease and senile dementia. Other uses of sibutramine are given in PCT publications WO 95/20949, WO 95/21615, WO 98/11884, WO 98/13033. Optically pure enantiomers of sibutramine are also among the subjects of development. For example, PCT WO 94/00047 and 94/00114 provide methods for treating depression and related diseases using (+)-and (-)-enantiomers of sibutramine, respectively.

Sibutramine is rapidly absorbed into the gastrointestinal tract after oral administration and undergoes extensive first-pass metabolism, in which the first metabolites desmethylsibutramine and didesmethyl sibutramine are produced.

Desmethyl sibutramine and didesmethyl sibutramine are reported to be more potent in vitro noraderlin and 5-hydroxytryptamine (5HT; serotonin) recombination inhibitors than sibutramine (Stock, MJ, Int'l J.). Obesity , 21 (Supp. 1) : S25-S29 (1997)). However, sibutramine and its metabolites are serotonin receptors (5-HT ₁ , 5-HT _1A , 5-HT _1D , 5-HT _2A , 5-HT _2C ), aderulin receptors, dopamine receptors, muscarinic receptors, histamine It shows little affinity for a wide range of neurotransmitter receptors, including receptors, glutamic acid receptors, and benzodiazepines.

Sibutramine has a variety of side effects ( Physician's Desk Reference ^® 1494-1498 (53 ^rd ed., 1999)). In addition to the known effects and therapeutic drawbacks of sibutramine, these side effects may include erectile dysfunction, mood disorders, weight gain or obesity, brain function disorders, pain, OCD, substance abuse, chronic diseases, anxiety, eating disorders, migraine headaches, and incontinence. There is a need for the discovery of compounds and compositions that can be used for the treatment or prevention of diseases. In particular, there is a need for compounds and compositions that can be used to treat or prevent such diseases and disorders without causing side effects associated with sibutramine.

3. Summary of the Invention

The present invention relates to methods, pharmaceutical compositions, and dosage forms for the treatment and prevention of diseases alleviated by inhibiting neuronal monoamine uptake in animals, including humans. Examples of such disorders include, but are not limited to, erectile dysfunction, mood disorders, weight gain or obesity, cerebral dysfunction, pain, obsessive compulsive, drug abuse, chronic disease, anxiety, eating disorders, migraine headaches, and incontinence. The method of the present invention is to administer a therapeutic or prophylactically effective amount of a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate or clathrate thereof, to a patient in need thereof. It is composed.

The present invention also includes a method of treating or preventing erectile dysfunction, which method comprises a therapeutically or prophylactically effective amount of a dopamine reuptake inhibitor and a 5-HT ₃ antagonist in a patient in need of such treatment or prevention. And additional administration.

The pharmaceutical composition of the present invention consists of a therapeutically or prophylactically effective amount of a neuronal monoamine reuptake inhibitor. Suitable neuronal monoamine reuptake inhibitors include, but are not limited to apomorphine, racemic and optically pure sibutramine metabolites, and pharmaceutically acceptable salts, solvates, clathrates thereof. The pharmaceutical composition of the present invention may further contain other drugs, including 5-HT ₃ antagonists.

The present invention includes the use of racemic and optically pure sibutramine metabolites as effective dopamine, serotonin, and norepinephrine reuptake inhibitors. Racemic and optically pure sibutramine metabolites include (+)-desmethylsibutramine, (-)-desmethylsibutramine, (±) -desmethylsibutramine, (+)-didesmethylsibutramine, (-)-didesmethyl Sibutramine, (±)-didesmethylcibutramine, but is not limited to these.

The present invention relates to methods and compositions for inhibiting re-receipt of neuronal monoamines (eg, dopamine, serotonin, norepinephrine). Accordingly, the present invention provides a method of treating or preventing a disease that is alleviated by inhibiting neuronal monoamine recombination, which method provides a therapeutic or prophylactic effect of a dopamine recombination inhibitor in a patient in need thereof. It consists in administering additional amounts. Suitable neuronal monoamine reuptake inhibitors are racemic and optically pure sibutramine metabolites and their pharmaceutically acceptable salts, solvates, clathrates.

In this article, "treating or preventing a disease that is alleviated by inhibiting neuronal monoamine recombination" refers to alleviation of abnormalities associated with abnormal neuronal monoamine levels. Disorders that are alleviated by inhibiting neuronal monoamine recombination include erectile dysfunction, mood disorders, weight gain or obesity, cerebral disease, pain, obsessive compulsive use, drug abuse, chronic disease, anxiety, eating disorders, migraine headaches, and incontinence, It is not limited to these.

A first embodiment of the present invention relates to a method for treating or preventing erectile dysfunction, which method is a therapeutic or prophylactic treatment of dopamine reuptake inhibitors and 5-HT ₃ antagonists in patients in need of such treatment or prevention. And additionally administering an effective amount. Suitable dopamine reuptake inhibitors include, but are not limited to, apomorphine, sibutramine, racemic and optically pure sibutramine metabolites, and pharmaceutically acceptable salts, solvates, clathrates thereof. Particularly suitable dopamine reuptake inhibitors are racemic and optically pure sibutramine metabolites. Suitable 5-HT ₃ antagonists include granistron (KYTRIL ^R ), metoglopramide (REGLAN ^R ), ondansetron (ZOFRAN ^R ), lenzapride, jacobopride, trophestron, optically pure stereoisomers, active Metabolites, and pharmaceutically acceptable salts, solvates, clathrates thereof, including, but not limited to.

In a suitable method of this embodiment, the dopamine reuptake inhibitor is administered transdermally or mucosally (eg, nasal, sublingual or oral). In a more suitable method embodiment, the dopamine reuptake inhibitor and the 5-HT ₃ antagonist are coadministered transdermally or mucosally.

A second embodiment of the present invention relates to a method for treating or preventing erectile dysfunction, which method comprises a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt thereof, in a patient in need of such treatment or prevention, It consists of administering a therapeutic or prophylactically effective amount of a solvate or clathrate. In a suitable method of this embodiment, the racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate or clathrate thereof, is administered transdermally or mucosally.

A third embodiment of the present invention relates to a method of treating or preventing a mood disorder, which method comprises a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvent thereof in a patient in need of such treatment or prevention. Consisting of administering a therapeutic or prophylactically effective amount of the compound or clathrate. Mood disorders include depression, such as depression, attention deficit disorder (including attention deficit disorder due to hyperactivity and attention deficit / hyperactivity disorder), bipolar and manic disorders, emotional disorders, and circulatory disorders. It is not limited. In this article, "Attention Deficit Disorder" (ADD), "Attention Deficit Disorder Due to Hyperactivity" (ADDH), and "Attention Deficit Hyperactivity Disorder" (AD / HD) follow the meanings commonly used in the art (Diagonostic and Statistical Mannual of Mental Disorders, Fourth Ed., American Psychatric Association, 1997 (DSM-IV ^TM ), Diagonostic and Statistical Mannual of Mental Disorders, 3rd Ed., American Psychatric Association, 1981 (DSM-IV ^TM )).

Appropriate methods of the above embodiments relate to methods of treating or preventing attention deficit disorders, wherein the methods are racemic or optically pure sibutramine metabolites, or pharmaceutically acceptable salts, solvents thereof in patients in need of such treatment or prevention. Consisting of administering a therapeutic or prophylactically effective amount of the compound or clathrate. In the treatment or prevention of attention deficit disorders, the racemic or optically pure sibutramine metabolite is an optically pure sibutramine metabolite, more preferably (-)-desmethyl sibutramine or (-)-didesmethyl sibutramine.

Another suitable method of the above embodiments relates to a method for treating or preventing depression, which method comprises a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvent thereof in a patient in need of such treatment or prevention. Consisting of administering a therapeutic or prophylactically effective amount of the compound or clathrate. In this article, "treating or preventing depression" refers to relief of emotional changes, intense sadness, despair, mental retardation, loss of consciousness, pessimistic anxiety, anger, and self-degradation. Physical changes can also be alleviated or prevented in this way, including but not limited to insomnia, loss of appetite, decreased energy and sexual impulses, and abnormal hormonal 24-hour rhythms.

 A fourth embodiment of the present invention relates to a method of treating or preventing weight gain or obesity, which method comprises a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt thereof, in a patient in need thereof. It consists of administering a therapeutically or prophylactically effective amount of a solvate or clathrate. In this article, "treating or preventing weight gain or obesity" refers to weight loss, weight loss, weight loss, and prevention of weight gain, which is caused by unnecessary food consumption.

A fifth embodiment of the present invention relates to a method for treating or preventing a brain dysfunction, which method comprises a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt thereof, in a patient in need of such treatment or prevention. And administering a therapeutic or prophylactically effective amount of a solvate or clathrate. Brain disorders include senile dementia, Alzheimer's dementia, amnesia, forgetfulness, difficulty in consciousness, unconsciousness, poor attention, speech impairment, Parkinson's disease, Rennox syndrome, autism, epilepsy, schizophrenia, and hypermotor syndrome It is not limited to. Cerebral dysfunctions include diseases that are selected from cerebrovascular diseases (e.g., cerebral infarction, cerebral hemorrhage, atherosclerosis, cerebrovascular thrombosis, head injury) and disorders of consciousness, senile dementia, unconsciousness, poor attention, speech disorder This may be induced by factors that are not limited to these. In this article, "treating or preventing cerebral dysfunction" refers to the reduction or prevention of one or multiple symptoms associated with cerebral dysfunction.

A sixth embodiment of the present invention relates to a method for treating or preventing pain, including chronic pain, which method comprises a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable thereof, in a patient in need of such treatment or prevention. It consists in administering a therapeutically or prophylactically effective amount of a possible salt, solvate or clathrate.

A seventh embodiment of the present invention relates to a method of treating or preventing OCD, wherein the method comprises a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvent thereof in a patient in need of such treatment or prevention. Consisting of administering a therapeutic or prophylactically effective amount of the compound or clathrate.

An eighth embodiment of the present invention relates to a method of treating or preventing drug abuse, wherein the method comprises a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt thereof, in a patient in need of such treatment or prevention, It consists of administering a therapeutic or prophylactically effective amount of a solvate or clathrate. In this article, "drug abuse" includes the abuse of drugs or alcohol and the resulting physical or mental addiction. "Drug abuse" follows the meaning commonly used in the art (DSM-IV ^™ , DSM-III ^™ ).

Suitable methods in this embodiment are methods for treating or preventing cocaine or heroin abuse.

A ninth embodiment of the present invention relates to a method for treating or preventing nicotine poisoning, the method comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt thereof, in a patient in need of such treatment or prevention, It consists of administering a therapeutic or prophylactically effective amount of a solvate or clathrate. Nicotine addiction includes all known forms of nicotine addiction, such as cigarette, cigar or pipe smoking, and tobacco addiction.

A tenth embodiment of the present invention relates to a method of inducing smoking cessation, said method comprising the treatment of racemic or optically pure sibutramine metabolites, or pharmaceutically acceptable salts, solvates or clathrates thereof in a smoking patient. It consists of administering a therapeutically effective amount.

In a suitable method of this embodiment, the racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, clathrate thereof, is administered orally, mucosally or transdermally. In a more suitable method, the racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate or clathrate thereof, is administered transdermally.

Another suitable method in this embodiment relates to a method of inducing smoking cessation, which method comprises a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate or clathrate and nicotine thereof in a smoking patient. It further comprises administering a therapeutically effective amount of. Preferably, the racemic or optically pure sibutramine metabolites, or pharmaceutically acceptable salts, solvates or clathrates thereof and nicotine are administered orally, mucosally or transdermally. More preferably, racemic or optically pure sibutramine metabolites, or pharmaceutically acceptable salts, solvates or clathrates thereof and nicotine are administered transdermally.

Another method in this embodiment relates to a method for treating or preventing weight gain associated with smoking cessation, which method comprises a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable thereof, in a patient in need of such treatment or prevention. It further consists of administering a therapeutically effective amount of a possible salt, solvate or clathrate and nicotine.

An eleventh embodiment of the present invention relates to a method for treating or preventing a chronic disease selected from narcolepsy, chronic fatigue syndrome, seasonal mood disorders, myofascial pain, premenstrual syndrome (or premenstrual discomfort disorder). The method consists of administering to a patient in need of such treatment or prevention a therapeutic or prophylactically effective amount of a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate or clathrate thereof. .

Suitable methods of this embodiment are methods for treating or preventing premenstrual syndrome, narcolepsy, chronic fatigue.

A twelfth embodiment of the present invention relates to a method of treating or preventing anxiety, the method comprising racemic or optically pure sibutramine metabolites, or pharmaceutically acceptable salts, solvents thereof in a patient in need of such treatment or prevention. Consisting of administering a therapeutic or prophylactically effective amount of the compound or clathrate.

A thirteenth embodiment of the present invention relates to a method of treating or preventing a dietary disorder, wherein the method comprises racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt thereof, in a patient in need of such treatment or prevention, It consists of administering a therapeutically or prophylactically effective amount of a solvate or clathrate.

A fourteenth embodiment of the present invention relates to a method of treating or preventing migraine, which method comprises a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvent thereof in a patient in need of such treatment or prevention. Consisting of administering a therapeutic or prophylactically effective amount of the compound or clathrate.

In this article, "OCD,""menstrualsyndrome"."Anxiety","eatingdisorders"."Migraine" follows the conventional meaning in the art (DSM-IV ^™ , DSM-III ^™ ). "Method of treating or preventing" in these diseases means a method of alleviating, preventing or alleviating the symptoms or effects associated with these diseases.

A fifteenth embodiment of the present invention relates to a method of treating or preventing incontinence, wherein the method comprises a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt thereof, in a patient in need of such treatment or prevention, It consists of administering a therapeutic or prophylactically effective amount of a solvate or clathrate. In particular, racemic or optically pure sibutramine metabolites can be used to treat defecation incontinence, stress incontinence (“SUI”), bladder disability, urge incontinence, passive incontinence, first class incontinence.

In this article, "treating or preventing urinary incontinence" refers to a pathological condition that alters sphincter control, loss of cognitive function, overexpansion of the bladder, hyperreflective-bladder contraction or involuntary urethral relaxation, muscle weakness or neurological abnormality associated with the bladder. By treatment, prevention or alleviation of incontinence symptoms, including involuntary discharge, drip or leakage of stools or urine due to one or more causes, including but not limited to these.

A suitable method in this embodiment is a method of treating or preventing stress incontinence. In another suitable method of the above embodiments, the patient is an elderly man over 50 years old or a child under 13 years old.

A sixteenth embodiment of the present invention relates to pharmaceutical compositions and dosage forms consisting of racemic or optically pure sibutramine metabolites, or pharmaceutically acceptable salts, solvates or clathrates thereof. These pharmaceutical compositions and dosage forms are particularly useful in the methods described above. For example, the dosage forms of the present invention are suitable for oral, mucosal (eg nasal, sublingual, oral, rectal, vaginal), extra-intestinal (eg intravenous and intramuscular), transdermal or subcutaneous administration. Suitable dosage forms for the present invention are suitable for oral, mucosal or transdermal administration.

Suitable racemic and optically pure sibutramine metabolites include (+)-desmethyl sibutramine, (-)-desmethyl sibutramine, (±) -desmethyl sibutramine, (+)-didesmethyl sibutramine, (-)-dides Methylsibutramine, (±) -didesmethylcibutramine, but are not limited to these.

* Optically pure sibutramine metabolite is most preferred. "Optically pure" as used herein means that the composition is based on the total weight of the active ingredient of at least 90% by weight of the desired stereoisomer, preferably at least 95% of the desired stereoisomer by weight, more preferably at least 99% by weight. It means that it contains the desired stereoisomer. For example, optically pure (+)-desmethylsibutramine is practically free of (-)-desmethylsibutramine. By "substantially free" in this article is meant that the composition has less than 10% by weight, preferably less than 5% by weight, more preferably less than 1% by weight of the compound.

Pharmaceutically acceptable salts, solvates or clathrates of racemic and optically pure sibutramine metabolites may be used in the methods, pharmaceutical compositions, and dosage forms of the present invention. As used herein, "pharmaceutically acceptable salts" refers to salts made from pharmaceutically acceptable non-toxic inorganic or organic acids. Inorganic acids include, but are not limited to, hydrochloric acid, bromic acid, iodic acid, nitric acid, sulfuric acid, phosphoric acid. Organic acids include, but are not limited to, aliphatic acids, aromatic acids, carboxylic acids, sulfonic organic acids, and the sulfonic organic acids include formic acid, acetic acid, propionic acid, succinic acid, benzene camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, and ise. Tionic acid, lactic acid, malic acid, slime acid, tartaric acid, para-toluenesulfonic acid, glycolic acid, glucuronic acid, maleic acid, furoic acid, glutamic acid, benzoic acid, anthranilic acid, salicylic acid, phenylacetic acid, mandelic acid, embon ( Pamo) acid, methanesulfonic acid, ethanesulfonic acid, pantothenic acid, benzenesulfonic acid, stearic acid, sulfanilic acid, alginic acid, galacturonic acid, but are not limited to these. Particularly suitable acids are bromic acid, hydrochloric acid, phosphoric acid, sulfuric acid, of which hydrochloric acid is most suitable.

In each method of the invention, the sibutramine metabolite, or a pharmaceutically acceptable salt, solvate or clathrate thereof, may be further administered with one or a plurality of pharmacologically active compounds; In other words, the sibutramine metabolite and one or more pharmacologically active compounds are administered in any suitable route (eg oral, transdermal or mucosal) in admixture, individually simultaneously or sequentially. In addition, suitable pharmaceutical compositions and dosage forms of the present invention may contain pharmaceutically acceptable excipients or one or more additional pharmacologically active compounds.

Additional pharmacologically active compounds that can be used in the methods and compositions of the present invention include drugs that act on the central nervous system (“CNS”), such as 5-HT (eg, 5-HT ₃ and 5-HT _1A ) action. Substances and antagonists; Selective serotonin reuptake inhibitors (“SSRIs”); Hypnotics and sedatives; Drugs to treat psychosis, including antipsychotics and neuroleptics, anti-anxiety drugs, antidepressants, mood-stabilizing agents; CNS stimulants (eg amphetamines); Dopamine receptor agonists; Antimony drugs; Airborne drugs; Cardiovascular drugs (eg, beta blockers and receptor antagonist convertase inhibitors); Antiviral agents; Antifungal agents; Anticancer agents are included, but are not limited to these.

More specific drugs that act on the CNS include SSRIs, benzodiazepines, tricycle antidepressants, antipsychotics, anxiolytics, β-adrenergic antagonists, 5HT _1A receptor antagonists, 5-HT ₃ receptor antagonists, It is not limited to these. More specific drugs that act on the CNS include, but are not limited to, lorazepam, geocetin, olanzapine, respiradon, buspyrone, hydroxyzine, and ballium.

Selective serotonin reuptake inhibitors are compounds that inhibit central nervous system reuptake of serotonin while showing limited affinity for other neuroactive receptors. Examples of SSRIs include citalopram (CELEXA ^® ); Fluoxetine (PROZAC ^® ), fluvoxamine (LUVOX ^® ); Paroxetine (PAXIL ^® ) sertraline (ZOLOFT ^® ); Benilafaxine (EFFEXOR ^® ); Optically pure stereoisomers, active metabolites, and pharmaceutically acceptable salts, solvates, clathrates thereof, but are not limited to these.

Benzodiazepines compounds that can be used in the methods and compositions of the present invention include, but are not limited to, those described in Goodman & Gilman, The Pharmacological Basis of Therapeutics, 362-373 (9 ^th ed. McGraw-Hill, 1996). Examples of specific benzodiazepines include alprazolam, brotizolam, chlordiazepoxide, clovazam, clonazepam, clolazepart, demoxamepam, diazepam, etazolam, flumazenyl, flurazzepam, halazepam, Lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, lepazepam, quasepam, temazepam, triazolam, pharmaceutically active metabolites and stereoisomers thereof, and pharmaceutically acceptable salts, solvates, clathrates thereof Although a compound is mentioned, It is not limited to these. The trade names of some of the compounds are given below.

Alprazolam is sold under the trade names of chemical name 8-chloro-1-methyl-6-phenyl-s- -4H-triazole [4,3-α] [1,4] benzodiazepine as, XANAX ^®. XANAX ^® is prescribed for the management of anxiety disorders (a disorder that almost corresponds to the diagnosis of general anxiety disorders of DSM-III ^TM ) or for the temporary relief of anxiety symptoms ( Physician's Desk Reference). ^® 2516-2521 (53 ^rd ed., 1999)). Chloro dia jepok seed hydrochloride is sold under the trade names of chemical name 7-chloro-2- (methylamino) -5-phenyl -3H-1,4- benzodiazepine-4-oxide hydrochloride, LIBRIUM ^®. LIBRIUM ^® is prescribed for the management or control of anxiety disorders, acute alcohol withdrawal symptoms, and relief from preoperative concerns and anxiety ( Physician's Desk Reference ^® 1369-1370 (53 ^rd ed., 1999)).

Clonazepam is sold under the trade name KLONOPIN® under the chemical name 5- (2-chlorophenyl) -1,3-dihydro-7-nitro-2H-1,4-benzodiazepine-2-one. KLONOPIN® is useful alone or as an adjunct to the treatment of Lennox-Gasto syndrome (variable small seizures), asexual seizures, and hepatic seizures. KLONOPIN® is prescribed for the treatment of panic disease with or without agoraphobia, as defined in DSM-IVTM (Physician's Desk Reference ® 2688-2691 (53rd ed., 1999)).

Chlorasepart bipotassium salt has the chemical name 7-chloro-2,3-dihydro-2,2-dihydroxy-5-phenyl-1H-1,4-benzodiazepine-3-carboxylated potassium, TRANXENE ^® It is sold under the brand name. TRANXENE ^® is an adjuvant therapy for the management of partial seizures and alleviation of symptoms of acute alcohol withdrawal. It is prescribed for the management of anxiety or temporary relief of anxiety symptoms ( Physician's Desk Reference ^® 475-476 (53 ^rd ed., 1999).

Diazepam is sold under the trade name VALIUM ^® under the chemical name 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one. VALIUM ^® is prescribed for the management of anxiety or temporary relief of anxiety symptoms ( Physician's Desk Reference ^® 2735-2736 (53 ^rd ed., 1999)).

Estazolam has the chemical name 8-chloro-6-phenyl-4H-s-triazole [4-3-α] [1,4] benzodiazepine and is sold under the trade name PROSOM ^™ . PROSOM ^™ is prescribed for short-term management of insomnia, characterized by difficulty sleeping, frequent nighttime or early morning blindness ( Physician's Desk Reference ^® 473-475 (53 ^rd ed., 1999)).

Flumazenyl has the chemical name ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazole [1,5-α] [1,4] benzodiazepine-3-carboxylate Sold under the trade name ROMAZICON ^® . ROMAZICON ^® is prescribed for complete or partial alleviation of the anesthetic effects of benzodiazepines, or for the management of benzodiazepine overdose when general anesthesia with or retained benzodiazepines for diagnostic and therapeutic procedures ( Physician's Desk Reference ^® 2701-2704 ( 53 ^rd ed., 1999).

Hydrochloride of flulazepam has the chemical name 7-chloro-1- [2- (diethylamino) ethyl] -5- (o-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine-2 -Raw bichloride, sold under the trade name DALMANE ^® . DALMANE ^® is a hypnotic agent useful in the treatment of insomnia characterized by difficulty sleeping, frequent nighttime or early morning snowiness ( Physician's Desk Reference ^® 2520 (52 ^rd ed., 1998)).

Lorazepam has the chemical name 7-chloro-5- (o-chlorophenyl) -1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepine-2-one, sold under the trade name ATIVAN ^® . have. ATIVAN ^® is prescribed for the management of anxiety disorders or for the temporary relief of depression-related anxiety symptoms ( Physician's Desk Reference ^® 3267-3272 (53 ^rd ed., 1999)).

The hydrochloride salt of midazolam is chemical name 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazole [1,5-α] [1,4] benzodiazepine hydrochloride, under the trade name VERSED ^® . It is sold. VERSED ^® is prescribed for preoperative anesthesia / anxiety removal / forgetfulness and general anesthesia ( Physician's Desk Reference ^® 3267-3272 (53 ^rd ed., 1999)).

Oxazepam is sold under the trade name SERAX ^® under the chemical name 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4benzodiazepine-2-one. SERAX ^® is prescribed for the management of anxiety disorders or for temporary relief of anxiety symptoms ( Physician's Desk Reference ^® 3267-3272 (53 ^rd ed., 1999)).

Cuasepam has the chemical name 7-chloro-5- (o-fluoro-phenyl) -1,3-dihydro-1- (2,2,2-trifluoroethyl) -2H-1,4--benzodiazepine-2 Thion, sold under the trade name DORAL ^® . DALMANE ^® is prescribed for the treatment of insomnia, which is characterized by difficulty sleeping, frequent nighttime or early morning blindness ( Physician's Desk Reference ^® 2958 (53 ^nd ed., 1998)).

Temazepam is sold under the trade name RESTORIL ^® under the chemical name 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one. . RESTORIL ^® is prescribed for short-term treatment of insomnia ( Physician's Desk Reference ^® 2075-2078 (53 ^rd ed., 1999)).

Triazolam has the chemical name 8-Chloro-6- (o-chlorophenyl) -1-methyl-4H-s-tria-solo- [4,3-α] [1,4] -benzodiazepine, trade name HALCION ^® It is sold. HALCION ^® is prescribed for short-term treatment of insomnia ( Physician's Desk Reference ^® 2490-2493 (53 ^rd ed., 1999)).

In order to treat or prevent any disease, a clinician, physician or psychiatrist may combine any of the compounds with racemic or optically pure sibutramine metabolites, or pharmaceutically acceptable salts, solvates or clathrates thereof. It can be easily recognized whether to mix.

As mentioned above, disorders that can be treated or prevented by mixing racemic or optically pure sibutramine metabolites, or their pharmaceutically acceptable salts, solvates or clathrates, and benzodiazepines may include the mood disorders described in this article (eg , Depression), anxiety, eating disorders, brain dysfunction, but not limited to these.

The invention also includes pharmaceutical compositions and methods of using the same, including racemic or optically pure sibutramine metabolites, or pharmaceutically acceptable salts, solvates, clathrates and antipsychotics thereof.

Antipsychotics are mainly used to manage patients with psychosis or other serious mental illnesses that are manifested by excitement and heterosexuality. These drugs possess clinically useful properties, including anti-hist and antihistamine effects and the ability to enhance analgesia, anesthesia, and general anesthesia. Specific antipsychotics are tricycle antipsychotics, which are divided into three subtypes: phenothiazine, thioxanthene, and other heterocycle compounds, all of which can be used in the methods and compositions of the present invention (Goodman & Gilman, The Pharmacological Basis of Therapeutics, 404 (9 ^th ed. McGraw-Hill, 1996)).

Specific tricycle antipsychotic compounds include chlorpromazine, mesozinazine, thiolidazine, acetophenazine, flufenazine, perphenazine, trifluoroperazine, chlorproticsen, thioticsen, clozapine, haloperidol, and loxapine , But includes, but is not limited to, molydondon, pimozide, risperidone, desipramine, pharmaceutically active metabolites and stereoisomers thereof, and pharmaceutically acceptable salts, solvates and clathrates thereof. The trade names of some of these compounds are given below.

Chlorpromazine is sold under the trade names of chemical name 10- (3-dimethylaminopropyl) -2-chloro-Fe as phenothiazine, THORAZINE ^®. THORAZINE ^® is prescribed for the management of symptoms of mental illness ( Physician's Desk Reference ^® 3101-3104 (53 ^rd ed., 1999)).

The besylate salt of mesodazine is sold under the trade name SERENTIL ^® under the chemical name 10- [2 (1-methyl-2-piperidyl) ethyl] -2-methyl-silfinyl) -phenothiazine. SERENTIL ^® is prescribed for the treatment of behavioral problems, alcoholism, and psychological symptoms in schizophrenia, mental retardation and chronic cerebral syndrome ( Physician's Desk Reference ^® 764-766 (53 ^rd ed., 1999)).

FER phenazine chemical name is 4- [3- (2-chloro-phenothiazin-10-yl) -propyl] sold under the trade name of 1-yl-piperazine in ethanol, TRILAFON ^®. TRILAFON ^® is prescribed for the management of mental illness symptoms and for controlling severe motion sickness and vomiting in adults ( Physician's Desk Reference ^® 2886-2888 (53 ^rd ed., 1999)).

Trifluoroperazine has the chemical name 10- [3- (4-methyl-1-piperazinyl) -propyl] -2- (trifluoromethyl) -10H-phenothiazine, sold under the trade name STELAZINE ^® . . STELAZINE ^® is prescribed for the management of mental illness and for short-term treatment of general non-mental anxiety ( Physician's Desk Reference ^® 3092-3094 (53 ^rd ed., 1999)).

Thio tiksen chemical name is N, N- dimethyl-9- [3- (4-methyl-1-piperazinyl) - propylidene] sold under the trade names of X thioxanthone-2-sulfonic acid amide with, NAVANE ^®. NAVANE ^® is prescribed for the management of symptoms of mental illness ( Physician's Desk Reference ^® 2396-2399 (53 ^rd ed., 1999)).

Clozapine is sold under the trade names of chemical name 8-chloro-11 (4-Methyl-1-piperazinyl) -5H- dibenzo [b, e] [1,4] diazepine with, CLOZATIL ^®. CLOZATIL ^® is prescribed for the management of severe schizophrenic patients who do not adequately respond to standard antipsychotic medications ( Physician's Desk Reference ^® 2004-2009 (53 ^rd ed., 1999)).

Haloperidol is sold under the trade name HALDOL ^® under the chemical name 4- [4- (p-chlorophenyl)]-4-hydroxy-piperidonol-4'-fluorobutyrophenone. HALDOL ^® is prescribed for the management of patients requiring long-term extra-intestinal antipsychotic treatment ( Physician's Desk Reference ^® 2190-2192 (53 ^rd ed., 1999)).

Roxapin is sold under the trade name LOXITANE ^® under the chemical name 2-chloro-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1-4] oxampinin. LOXITANE ^® is prescribed for the management of mental illness symptoms ( Physician's Desk Reference ^® 3224-3225 (53 ^rd ed., 1999)).

Sold under the trade name of a circle hydrochloride, MOBAN ^® - Moline money chemical name of 3-ethyl-6,7-dihydro-2-methyl-5- (morpholino-methyl) indol -4 (5H). MOBAN ^® is prescribed for the management of symptoms of mental illness ( Physician's Desk Reference ^® 978-979 (53 ^rd ed., 1999)).

Pimozids have the chemical name 1- [1- [4,4-bis (4-fluorophenyl) butyl] 4-piperidinyl] -1,3-dihydro-2H-benzimidazole-2-one, ORAP Sold under the trade name ^® . ORAP ^® is prescribed for the management of severe schizophrenic patients who do not respond sufficiently to standard antipsychotic medications ( Physician's Desk Reference ^® 1054-1056 (53 ^rd ed., 1999)).

Risperidone has the chemical name 3- [2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -6,7,8,9-tetrahydro- 2-methyl-pyrido -4H- as [1,2-a] pyrimidin-4-membered, and is sold under the trade name of RISPERDAL ^®. RISPERDAL ^® is prescribed for the management of symptoms of mental illness ( Physician's Desk Reference ^® 1432-1436 (53 ^rd ed., 1999)).

Plastic decitex seeds hydrochloride chemical name 5H- dibenz [b f] azepine-5-pro waves Min -10,11- dihydro multi -N- methyl-are sold under the trade name of a mono-hydrochloride, NORPRAMIN ^®. NORPRAMIN ^® is prescribed for the treatment of depression ( Physician's Desk Reference ^® 1332-1334 (53 ^rd ed., 1999)).

Mood disorders in diseases that can be treated or prevented with racemic or optically pure sibutramine metabolites, or pharmaceutically acceptable salts, solvates or clathrates and antipsychotic compounds (especially tricycline antipsychotic compounds) (Eg, depression), anxiety, eating disorders, brain dysfunction (eg, schizophrenia), but are not limited to these.

The present invention also provides a pharmaceutical composition comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate or clathrate thereof and a mixture of 5-HT _1A receptor antagonist or β-adrenergic antagonist. Compositions and methods of using the same. 5-HT _1A receptor antagonists or β-adrenergic antagonists that can be used in the methods and compositions of the present invention include alprenolol; WAY 100135; Spiferon; Pindolol; (S) -UH-301; Fenbutolol; Propranolol; Tertatolol; US Patent No. A compound of Formula I as disclosed in 5,552,429; Pharmaceutical active metabolites and stereoisomers thereof; Pharmaceutically acceptable salts, solvates, clathrates thereof, but are not limited to these.

Alprenolol has the chemical name 1- (1-methylethyl) amino-3- [2- (2-propenyl) phenoxy] -2-propanol and U.S. Patent No. 3,446,325.

WAY 100135 has the chemical name N- (t-butyl) -3- [4- (2-methoxyphenyl) -piperazin-1-yl] -2-phenylpropaneamide, disclosed in US Pat. No. 4,988,814 (Cliffe et al., J. Med. Chem., 36: 1509-1510 (1993).

Spiferon has the chemical name 8- [4- (4-fluorophenyl) -4-oxobutyl] -1-phenyl-1,3,8-triazaspiro [4,5] decane-4-one, US Pat. No. 3,155,669 and 3,155,670 (see Middlmiss et al., Neurosci. And Biobehav. Rev., 16: 75-82 (1992)).

Pindolol has the chemical name 4- (2-hydroxy-3-isopropylaminopropoxy) -indolo, US Pat. 3,471,515 (see Freshfield et al., Neurochem. Res., 21 (5): 557-562 (1996)).

(S) -UH-301 has the chemical name (S) -5-fluoro-8-hydroxy-2-dipropylamino-tetraline, which is known to pharmacologists and chemists in the pharmaceutical arts (Hillyer et al. , J. Med. Chem., 33: 1541-44 (1990) and Moreau et al., Brain Res. Bull., 29: 901-04 (1992).

Fenbutolol has the chemical name 1- (t-butylamino) -2-hydroxy-3- (2-cyclopentyl-phenoxy) propane and is sold under the trade name LEVATOL ^® . LEVATOL ^® is prescribed for treating mild to moderate arterial hypertension ( Physician's Desk Reference ^® 2908-2910 (53 ^rd ed., 1999)).

Of propranolol hydrochloride it is sold under the trade names of chemical name 1-isopropylamino-3- (1-naphthalenyl) -2-propanol with hydrochloric acid, INDERAL ^®. INDERAL ^® is prescribed for hypertension management ( Physician's Desk Reference ^® 3307-3309 (53 ^rd ed., 1999)).

Tertatolol has a chemical name of 8- (3-t-butylamino-2-hydroxypropyloxy) -thiochrome, and U.S. Pat. Patent No. 3,960,891.

Diseases that can be treated or prevented with racemic or optically pure sibutramine metabolites, or pharmaceutical compositions consisting of pharmaceutically acceptable salts, solvates or clathrates and 5-HT _1A receptor antagonists include depression, obsessive compulsive disorder , But not limited to, eating disorders, high blood pressure, migraine, essential tremor, subaortic hypertrophy, pheochromocytoma. Specific diseases that can be treated or prevented are post-traumatic depressive disorders.

Diseases that can be treated or prevented with racemic or optically pure sibutramine metabolites, or pharmaceutical compositions consisting of pharmaceutically acceptable salts, solvates or clathrates and β-adrenergic antagonists, may be present after acute myocardial infarction. Depression is included, but not limited to these. Specific β-adrenergic antagonists include, but are not limited to, S ( -) pindolol, fenbutolol, propranolol.

The present invention also encompasses pharmaceutical compositions comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate or clathrate thereof and a benzodiazepine or non-tricycle drug and a method of using the same. . Examples of such additional pharmaceutically active compounds include olanzapine, buspyrone, hydroxyzine, geocetin, pharmaceutically active metabolites and stereoisomers thereof, and pharmaceutically acceptable salts, solvates and clathrates thereof. It is not limited to these.

Olanzapine has the chemical name 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3- b ] [1,5] benzodiazepine, sold under the trade name ZYPREXA ^® . ZYPREXA ^® is prescribed for the management of mental illness symptoms ( Physician's Desk Reference ^® 1641-1645 (53 ^rd ed., 1999)).

Buspirone hydrochloride has the chemical name 8- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -8-azaspiro- [4.5] decane-7,9-dione monohydrochloride Sold under the trade name BUSPAR ^® . BUSPAR ^® is prescribed for the management of anxiety disorders or for the temporary relief of anxiety symptoms ( Physician's Desk Reference ^® 823-825 (53 ^rd ed., 1999)).

Hydroxy spirit hydrochloride chemical name is 1- (p- chloro-benzhydryl) -4- sold under the trade name of [2- (2-hydroxyethoxy) ethyl] piperazine as the hydrochloride of, ATARAX ^®. ATARAX ^® is prescribed for alleviation of symptoms of anxiety and tension associated with psychiatric neuropathy, and is used as an adjuvant in an organic disorder with apparent anxiety ( Physician's Desk Reference ^® 2367-2368 (53 ^rd ed., 1999)).

Racemic or optically pure sibutramine metabolites, or pharmaceutically acceptable salts, solvates or clathrates thereof, and lorazepam, geocetin, olzapine, respiradon, buspyrone, hydroxyzine, ballium, pharmaceuticals thereof Diseases that can be treated or prevented with a pharmaceutical composition consisting of a combination of pharmaceutically active metabolites and stereoisomers and their pharmaceutically acceptable salts, solvates and clathrates include disorders of anxiety, depression, hypertension and attention deficit. But is not limited to these.

Racemic or optically pure sibutramine metabolites, or pharmaceutically acceptable salts, solvates or clathrates thereof, and all mixed compositions of one or more of the aforementioned pharmaceutically active compounds are useful and valuable, although certain mixed compositions of these are useful. This is particularly appropriate. Examples of suitable mixed compositions include racemic or optically pure sibutramine metabolites, or pharmaceutically acceptable salts, solvates or clathrates thereof and mixed compositions with one of the following:

Alprazolam; Quazpam; Alprenolol;

Brotizolam; Temazepam; WAY 100135;

Chlorodiazepoxide; Triazolam; Spiferon;

Clovazam; Chlorpromazine; S (-)-pindolol;

Clonazepam; Buckthorn minced; R (+)-pindolol;

Chlorasepart; Thiolidazine; Racemic pindolol;

Demoxepam; Acetophenazine; (S) -UH-301;

Diazepam; Flufenazine; Fenbutolol;

Estazolam; Perphenazine; Propranolol;

Flumazenyl; Trifluoroperazine; Tertatolol;

Flulazepam; Chlorproticsen; Desipramine;

Halazepam; Thiotices; Clonidine;

Lorazepam; Clozapine; Olanzapine;

Midazolam; Haloperidol; Methylphenidat;

Nitrazepam; Loxapine; Buspyrone;

Nordazepam; Molindon; Hydroxyzine;

Oxazepam; Fimozide; Geocetin;

Parazepam; Risperidone.

4.1. Synthesis of Sibutramine Metabolites

Racemic sibutramine, desmethylcibutramine, didesmethylcibutramine can be made by methods known in the art (US Patent No. 4,806,570; J. Med. Chem., 2540 (1993) (tosylation and azide substitution) Butler, D., J. Org. Chem., 36: 1308 (1971) (cycloalkylation in DMSO); Tetrahedron Lett., 155-528 (1980) (adding Grignard to benzene internal nitrile); Tetrahedron Lett. , 857 (1997) (adding OH to azide) Jeffery, JE, et al., J. Chem. Soc. Perkin. Trans 1,2583 (1996). Suitable methods for preparing racemic sibutramine are shown in Example 1 below.

Racemic sibutramine, desmethyl sibutramine and didesmethyl sibutramine can be made from each other. Suitable methods for preparing certain compounds from other compounds are shown in Examples 2, 3, and 8 below. Optically pure enantiomers of sibutramine can be made using techniques known in the art. A suitable technique is the decomposition by fractional crystallization of diastereomeric salts made with optically active degradation agents ("Enantiomers, Racemates and Resolutions," by J. Jacques, A. Collet, and SHWilen, (Wiley-Interscience, New York, 1981). SH Wilen, A. Collet, and J. Jacques, Tetrahedron , 2725 (1977); ELEliel Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and SH Wilen Tables of Resolving Agents and Optical Resolutions 268 (EL Eliel ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

Since sibutramine, desmethyl sibutramine and didesmethyl sibutramine are basic amines, optically pure chiral acid degradation agents are added to make diastereomeric salts of these compounds suitable for separation by fractional crystallization. Suitable disintegrating agents include, but are not limited to, optically pure tartaric acid, camphorsulfoic acid, mandelic acid, and derivatives thereof. Optically pure isomers of sibutramine, desmethyl sibutramine and didesmethyl sibutramine can be collected from diastereomers or mother liquors crystallized according to the solubility of the particular acid decomposition solution and acid enantiomer used. The identity and optical purity of the specific sibutramine or sibutramine metabolite thus collected can be determined by polarization or other analytical methods.

Racemic and optically pure sibutramine metabolites are preferably described in Jeffery, JE, et al., J. Chem. Soc. Perkin. It is synthesized directly by the method described in Trans 1, 2583 (1996). A suitable method of directly synthesizing racemic desmethyl sibutramine is to reduce the cyclobutanecarbonitrile (CCBC) to form an aldehyde intermediate, which is then reacted with an amine, for example methylamine. This method is applied in Example 4 below.

Another suitable method for the direct synthesis of racemic desmethylcybutramine is the reaction of CCBC with a compound of formula i-BuMX, where X is Br or I and M is selected from Li, Mg, Zn, Cr, Mn. Preferably, the compound is of formula i-BuMbBr. The product produced in this reaction is then converted to an intermediate consisting of aldehydes that are oxidized and bonded to a nitrogen atom, which is converted to desmethylsibutramine by adding Lewis acid to the intermediate. Suitable Lewis acids are selected from BH ₃ -THF, BF ₃ -THF, La (Oi-Pr) ₃ , Zr (Oi-Pr) ₄ , Ti- (Oi-Pr) ₂ Cl ₂ , SnCl ₄ , MgBr ₂ -OEt ₂ do. The most suitable Lewis acid is BF ₃ -THF. This method applies in Example 5.

Enantiomers of desmethylsibutramine can be degraded by the formation of chiral salts as described above. Suitable chiral acids used to form chiral salts include, but are not limited to, tartaric acid and mandelic acid. Suitable solvents when using tartaric acid include, but are not limited to, ethanol / water and isopropyl alcohol / water. When using mandelic acid the suitable solvent is ethyl acetate / hexanes. Degradation of desmethylsibutramine is shown in Examples 6 and 7 below.

A suitable method for the direct synthesis of racemic didesmethyl sibuturamine is the reaction of CCBC with a compound of formula i-BuMX, where X is Br or I and M is selected from Li, Mg, Zn, Cr, Mn . Preferably, the compound is of formula i-BuMbBr. The product produced in this reaction is then reduced under appropriate reaction conditions. This method applies in Example 9.

Enantiomers of didesmethyl sibutramine can be degraded by the formation of chiral salts as described above. Suitable chiral acids used to form chiral salts include, but are not limited to, tartaric acid. Suitable solvents include, but are not limited to acetonitrile / water / methanol and acetonitrile / methanol. Decomposition of didesmethyl sibutramine is shown in Examples 11 and 12 below.

4.2 Pharmaceutical Compositions and Methods of Use thereof

The degree of prophylactic or therapeutic dose of the active ingredient in short-term or long-term management of the disease or condition will depend upon the severity and route of administration of the disease or condition to be treated. Dosage and frequency will also depend on age, weight, response, and patient's past treatment history. Those skilled in the art can easily select a suitable regimen in view of these factors.

Suitable daily doses for the treatment or prevention of the diseases described in this article can be readily determined by those skilled in the art. The recommended amount of racemic or optically pure sibutramine metabolite is between 0.1 mg and 60 mg per day in a single dose or morning dose in the morning. Preferably, the daily dose is 2 mg to 30 mg, more preferably 5 mg to 15 mg.

Appropriate daily dosages of additional pharmaceutical active compounds that can be additionally administered with racemic or optically pure sibutrami metabolites are recommended in the literature and in Physician's Desk Reference ^® (53 ^rd ed., 1999). The dosage can be readily determined by one skilled in the art.

For example, the appropriate daily dosage range of 5-HT ₃ antagonist can be readily determined by one skilled in the art, depending on the factors mentioned above and the particular 5-HT ₃ antagonist used. In general, the total daily dose of 5-HT ₃ antagonist for the prophylaxis or treatment of the diseases disclosed in this article is 0.5 mg to 500 mg, preferably 1 mg to 350 mg, more preferably 2 mg to 250 mg. .

Preferably, therapeutic or prophylactic administration of the active compounds of the present invention begins with small doses, such as 2 mg to 8 mg sibutramine metabolite and optionally 15 mg to 60 mg 5-HT ₃ antagonist, if necessary Depending on the patient's overall response, single or divided doses will be increased to the recommended daily dose. Older people 65 years or older should be administered sibutramine metabolites in the range of 5 mg to 30 mg per day, depending on the patient's overall response. Doses outside these ranges may be used, and those of ordinary skill in the pharmaceutical arts will readily be able to determine this.

The doses and frequencies mentioned above are referred to in this article as "therapeutic effect". Included in the terms "prophylactic effect", "therapeutic or prophylactic effect". In terms of the amount of racemic or optically pure sibutramine metabolites, these terms include the amount of racemic or optically pure sibutramine metabolites that induce much less side effects associated with the administration of racemic sibutramine. Side effects associated with racemic sibutramine include: significant increase in supine and heart rate (including tachycardia), increased blood pressure (hypertension), increased psychomotor activity, dry mouth, tooth decay, constipation, dullness, dizziness, tension, pupillary band, Seizures, gallstones, kidney / liver dysfunction, fever, arthritis, excitement, leg cramps, hypertension, abnormal accidents, bronchitis, dyspnea, itching, amblyopia, menstrual disorders, ecchymosis / bleeding, interstitial nephritis, neuralgia But not limited to these ( Physician's Desk Reference ^® 1494-1498 (53 ^rd ed., 1999)).

Two or more active ingredients according to the method of the invention may be further administered simultaneously or sequentially. For example, dopamine recombination inhibitors and 5-HT ₃ antagonists may be mixed and administered separately simultaneously or sequentially.

Any suitable route of administration may be used to provide the patient with a therapeutically or prophylactically effective amount of the active ingredient. For example, oral, mucosal (eg, nasal, sublingual, oral, rectal, vaginal), extra-intestinal (eg, intravenous, intramuscular), transdermal, subcutaneous routes can be used. Suitable routes of administration include oral, transdermal and mucosal. As mentioned above, the active ingredient for the treatment or prevention of erectile dysfunction is preferably administered mucosally or transdermally. Pharmaceutical forms suitable for this route include, but are not limited to, transdermal patches, eye solutions, sprays, and aerosols. Transdermal compositions may take the form of creams, lotions or emulsions, which may be included in a suitable adhesive for application to the skin or in a transdermal patch in the form of a matrix or reservoir commonly used for this purpose in the art. have.

Suitable transdermal dosage forms are "reservoir" or "matrix" patches, which attach to the skin for a certain period of time, allowing the active ingredient to penetrate. For example, if the active ingredient is a sibutramine metabolite, the patch is applied for 24 hours to provide a dose of 0.1 mg to 60 mg per day. Preferred daily doses are 2 mg to 30 mg, more preferred daily doses are 5 mg to 15 mg. The patch can be replaced with a new patch if the active ingredient must be continuously administered to the patient.

Other dosage forms of the invention include tablets, caplets, sugars, lozenges, suspensions, suppositories, ointments, poultices (pastes), pastes, powders, bandages, creams, plasters, solutions, capsules, stretchable gelatin capsules, patches. But is not limited to these.

In one embodiment, the pharmaceutical compositions and dosage forms of the invention comprise dopamine reuptake inhibitors (eg racemic or optically pure sibutramine metabolites, or pharmaceutically acceptable salts, solvates or clathrates) and optionally additionally Pharmacologically active compounds (eg, 5-HT ₃ antagonists). Suitable racemic or optically pure sibutramine metabolites include (+)-desmethyl sibutramine, (−)-desmethyl sibutramine, (±) -desmethyl sibutramine, (+)-didesmethyl sibutramine, (−)-dides Methylsibutramine, (±) -didesmethylcibutramine. Pharmaceutical compositions and dosage forms may contain pharmaceutically acceptable carriers and other therapeutic ingredients known in the art.

In practice, the active ingredient may be combined with an intact mixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a variety of forms depending on the form of preparation suitable for administration. In the preparation of oral pharmaceutical compositions, in the case of oral liquid preparations (e.g. suspensions, solutions, elixirs) or aerosols, carriers may be used as a pharmaceutical medium such as water, glycols, oils, alcohols, seasonings, preservatives, colorants and the like. Can be used; Alternatively, in the case of oral solid preparations, starch, sugar, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents are used, and lactose is preferably used. For example, suitable carriers include powders, capsules, tablets, and solid oral formulations are preferred over liquid formulations.

Ease of administration makes tablets and capsules the most advantageous oral dosage forms, in which case pharmaceutical solid carriers are used. If desired, tablets may be coated by standard hydration or non-hydration techniques.

In addition to the conventional dosage forms described above, the active ingredient may be administered by controlled release means or delivery devices known in the art (US Patent Nos .: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,733,566). These dosage forms use the hydropropylmethyl cellulose, other polymer matrices, gels, penetrable membranes, osmotic devices, multilayer coatings, microparticles, liposomes, microporous or mixtures thereof to sustained or controlled release of one or more active ingredients. Thus, it can be used to provide the desired release profile in various ratios. Suitable controlled-release compositions known in the art, including those described above, can be readily selected and used as pharmaceutical compositions of the present invention. Accordingly, the present invention includes single unit dosage forms suitable for oral administration. Examples of such unit dosage forms include, but are not limited to, tablets, capsules, gelcaps, and controlled-release custom caplets.

All controlled-release pharmaceutical products have a common purpose in providing improved pharmacotherapy as compared to non-controlled products. In ideal drug treatment, the use of optimally designed controlled-release preparations is characterized by treating or controlling the disease with the least amount of drug for a minimum amount of time. Advantages of the controlled-release composition include: 1) expanding drug activity; 2) decreased frequency of drug administration; 3) Increased patient compliance. In addition, the controlled-release composition may affect the time of onset of action or other characteristics (eg, the blood level of the drug), and thus may affect the occurrence of side effects.

Most controlled-release compositions are designed to initially release a dose of drug that immediately exhibits the desired therapeutic effect, and then to continue to release other doses of the drug that maintain this level of therapeutic effect for an extended period of time. . To maintain a certain level of drug in the body, the drug must be released in the dosage form at a rate that can replace the amount of drug that is metabolized and released from the body. Controlled release of the active ingredient can be promoted by a variety of inducers, including but not limited to pH, temperature, enzymes, water or other physiological conditions or compounds.

Pharmaceutical compositions suitable for oral administration in the present invention may be presented in individual dosage forms (eg, capsules, cachets or tablets) or as aerosol sprays, each of which may be powders or granules, solutions, water-soluble or non-aqueous liquids, oil-in-water emulsions. Or a suspension in a water-in-oil emulsion, containing a predetermined amount of active ingredient. Such forms may be made by any pharmaceutical method, but all methods require the step of combining the active ingredient with a carrier containing one or more essential ingredients. Generally, the composition is made by mixing the liquid carrier, the finely divided solid carrier or both with the active ingredient homogeneously and intactly, and molding the product into the desired form if necessary.

For example, tablets may be made by compression or molding with one or a plurality of accessory ingredients. Compressed tablets may be made by compressing the active ingredient in a free-flowing form, such as a powder or granules, in a suitable machine, optionally with a binder, a lubricant, an inert diluent, a surfactant or a dispersant. Molded tablets can be made by molding in a suitable machine a mixture of an inert liquid diluent and a moist powder compound.

The present invention is lactose-free are contains a pharmaceutical composition as yakhyeong ^{(Physician's Desk Reference ® 1494 (} 53 rd ed, 1999).). However, because desmethyl sibutramine and didesmethyl sibutramine are secondary and primary amines, respectively, unlike conventional patented drugs, they are significantly decomposed over time when exposed to lactose. Thus, compositions of the present invention consisting of sibutramine metabolites preferably contain other single- or disaccharides other than lactose. "Lactose-free" in this article means that there is not enough lactose to substantially increase the rate of degradation of the active ingredient.

The lactose-free compositions of the present invention are known in the art and may contain excipients described in USP (XXI) / NF (XVI). In general, lactose-free compositions consist of pharmaceutically complementary and acceptable amounts of active ingredients, binders / fillers, lubricants. Suitable lactose-free dosage forms consist of the active ingredient, microcrystalline cellulose, pre-gelatinized starch, magnesium stearate.

The present invention also encompasses pharmaceutical anhydrous compositions and dosage forms consisting of the active ingredient, since water can facilitate the degradation of some compounds. For example, in the art, the addition of water (eg, 5%) is recognized as a means of long-term storage facilitating determining properties such as shelf-life or stability of the composition over time (Jens T, Carstensen, Drug Stability: Principles & Practice , 2d.Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80). In practice, water and heat accelerate decomposition. Therefore, the effect of water on the composition is very important because of the moisture generally encountered during manufacture, shipping, packaging, storage, shipping, and use of the composition.

Pharmaceutically anhydrous compositions and dosage forms of the invention can be prepared using anhydrous or low moisture retention components and low moisture or low humidity conditions. Where significant contact with moisture or moisture is expected during manufacture, packaging or storage, pharmaceutical compositions and dosage forms consisting of racemic or optically pure sibutramine metabolites containing lactose are preferably anhydrous.

Pharmaceutical anhydrous compositions should be prepared and stored so that anhydrous remains constant. Thus, anhydrous compositions are packaged in suitable kits containing materials known to prevent contact with water. Examples of suitable packaging include, but are not limited to, sealed foils, plastics, unit dose containers, foam containers, strip packs.

In this aspect, the present invention includes a method for preparing a pharmaceutical solid composition consisting of the active ingredient, which comprises the mixing of the active ingredient and excipients (e.g. lactose) under anhydrous or low moisture / humidity conditions, Wherein said component is substantially free of water. The method further includes packaging anhydrous or non-hygroscopic solid composition under low moisture conditions. Such conditions can be used to reduce the risk of contact with water, thereby preventing or minimizing degradation of the active ingredient.

Suitable binders for use in pharmaceutical compositions and pharmaceutical forms include corn starch, potato starch or other starches, gelatin, powdered tragacanth gum, guar gum, cellulose and its derivatives (e.g. ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, Sodium carboxymethylcellulose), polyvinyl pipolydone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose (e.g. Nos. 2906, 2910), microcrystalline cellulose, mixtures thereof, including but not limited to It is not limited.

Suitable microcrystalline cellulose forms are those sold by AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA, USA). This includes. Typical binders are mixtures of microcrystalline cellulose and sodium carboxymethyl cellulose (AVICEL RC-581). Suitable anhydrous or low humidity excipients or additives include AVICEL-PH-103 ^™ and starch 1500 LM.

Examples of fillers suitable for use in the pharmaceutical compositions and pharmaceutical forms of the present invention include talc, calcium carbonate (e.g. granules or powders), microcrystalline cellulose, powdered celluloses, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, Pre-gelatinized starch, mixtures thereof, but is not limited to these. In the pharmaceutical composition of the present invention, the binder / filler is present at 50-99 wt% of the pharmaceutical composition.

Disintegrants are used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. If too much disintegrant is used, the tablets disintegrate in the bottle. If too little of a disintegrant is used, it will not disintegrate and thus change the release rate and amount of active ingredient from the weak form. Therefore, the weak form of the compound of the present invention is prepared using an appropriate amount of disintegrant which does not adversely affect the release of the active ingredient. The amount of disintegrant used depends on the composition form and the route of administration, which one of ordinary skill in the art can readily determine. Generally, 0.5-15 wt% disintegrant, preferably 1-5 wt% disintegrant, may be used in pharmaceutical compositions.

Disintegrants that can be used to make pharmaceutical compositions and pharmaceutical forms of the present invention include agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium polyacrylic acid, sodium starch glycolate, potato or tapioca Starch, other starch, pre-gelatinized starch, clay, other algin, other cellulose, gum or mixtures thereof, including but not limited to these.

Lubricants that can be used to make pharmaceutical compositions and forms of the present invention include calcium stearate, magnesium stearate, mineral oil, mineral mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauric sulfate, talc Hydrated vegetable oils (e.g. peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar or mixtures thereof It is not limited to these. Examples of other lubricants include siloid silica gel (AEROSIL 200, WR Grace Co. of Baltimore, MD), solidified aerosols of synthetic silica (Degussa Co. of Plano, Texas), CAB-O-SIL (pyrogenic silicon dioxide, Cabot Co. of Boston, Mass) or mixtures thereof. Lubricants may be optionally added in amounts less than 1 wt% of the pharmaceutical composition.

The dosage forms of the invention, composed of sibutramine metabolites, contain 0.1 mg to 60 mg of the metabolite, or a pharmaceutically acceptable salt, solvate or clathrate thereof. For example, each tablet, cachet or capsule contains 0.1 mg to 60 mg of active ingredient. Most preferred tablets, sugars or capsules contain three doses, for example 10 mg, 20 mg or 30 mg of racemic or optically pure sibutramine metabolite (lactose-free tablets are the preferred dosage form).

The invention is specified with reference to the following examples. It will be apparent to those skilled in the art that many modifications can be made to the materials and methods without departing from the scope of the invention.

5. Examples

Examples 1-2 illustrate the preparation of racemic and optically pure sibutramine.

Examples 3-8 describe the preparation of desmethylsibutramine (DMS) in racemic and optically pure form. In each of these experiments, the enantiomeric purity of the DMS was determined using a Chirobiotic V analytical column (10 μm, 4.6 mm × 25 mm) with 20 mM ammonium acetate / IPA (65:35) as the mobile phase. The UV detector was set to 222 nm wavelength.

Examples 9-12 describe the preparation of didesmethyl sibutramine (DDMS) in racemic and optically pure form. In each of these experiments, the enantiomeric purity of DDMS was measured using a ULTRON ES-OVM analytical column (150 mm x 4.6 mm) with 0.01 M KH ₂ PO ₄ / MeOH (70:30) as the mobile phase. The UV detector was set to 200 nm wavelength.

Examples 13-14 illustrate methods of measuring the binding affinity of the compounds of the present invention and the binding affinity measured using these methods.

Finally, Example 15 illustrates an oral composition consisting of the compounds of the invention.

5.1. Example 1 Synthesis of Sibutramine

Synthesis of 1- (4-chlorophenyl) cyclobutanecarbonitrile

Chlorbenzylnitrile (30.3 g) and 1,3-dibromopropane (22.3 mL, 44.5 g) in a suspension of NaH (17.6 g 60%, washed with hexane) dissolved in dimethyl sulfoxide (150 mL) by mechanical stirring at room temperature. Was added for 1 hour. The reaction mixture was stirred for an additional hour and isopropyl alcohol (10 mL) was added slowly to remove excess NaH. Water (150 mL) was added. The reaction mixture was extracted with t-butylmethyl ether (MTBE) (2 x 200 mL) and the combined extracts were washed with water (3 x 200 mL), pickled in brine and dried over MgSO ₄ . The solvent was removed in a rotary evaporator and the final product was distilled to give the final compound (22 g, 56%) as a pale yellow oil (bp 110-120 ° C / 1.0 mm Hg). The product was characterized by ¹ H NMR.

Synthesis of 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine

The isobutyl magnesium bromide solution (2M, 108 mL) dissolved in diethyl ether (Aldrich) was concentrated to remove most ether. The residue was taken up in toluene (150 mL) and then nitrile (22 g) made as above was added. The reaction mixture was heated at 105 ° C. for 17 hours. The reaction mixture was cooled to room temperature and added to a NaBH ₄ slurry dissolved in isopropyl alcohol (450 mL). The reaction mixture was heated at reflux for 6 hours, cooled to room temperature and concentrated. The residue was diluted with water (350 mL) and extracted with ethyl acetate (3 x 200 mL). The combined extracts were washed with water (100 mL), dried (MgSO ₄ ) and concentrated to give 24.2 g crude product (83%).

Synthesis of Sibutramine Free Base

1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine (21.6 g) was added to formic acid (27 mL) and hydrophobic formaldehyde (46 mL). The reaction mixture was heated at 85-95 ° C. for 18 hours and cooled to room temperature. 30% NaOH was added until the reaction showed basic (pH> 11). The solution was extracted with chloroform (3 × 200 mL), the extracts were combined, washed with water, pickled and concentrated to give 15 g product.

Sibutramine HCl

Sibutramine freebase (2.25 g) was dissolved in MTBE (20 mL) and the solution was added to 20 mL 1M HCl in diethyl ether. The reaction mixture was stirred for 30 minutes and the solids were collected by filtration and dried to give 1.73 g product. The product was characterized by ¹ H NMR.

Decomposition of Sibutramine

12.3 g racemic sibutramine was dissolved in ethyl acetate (85 mL), to which 21.7 g L-dibenzyltin acid ("L-DBTA") of ethyl acetate (85 mL) solvent was added. The reaction mixture was heated to reflux and cooled to room temperature. White precipitate was collected (ca 85% ee of the salt). The solid was then suspended in 220 mL ethyl acetate and heated at reflux for 30 minutes. > 95% ee solid was obtained. The salt was further crystallized in isopropyl alcohol (450 mL) to give 11.3 g salt of> 99.3% ee (-)-sibutramine-L-DBTA (76% yield). Treatment of the salt with saturated aqueous NaHCO ₃ afforded a free base which was extracted with chloroform. The free base was treated with HCl / Et ₂ O as described above to give a (-)-sibutramine HCl salt. The optical rotation of the HCl salt was [α] = 3.15 (c = 0.9, H ₂ O), ¹ H NMR ¹³ C (CD ₃ OD), M ⁺ = 279. The cleaved mother liquor was treated with NaOH to give (+)-sibutramine predominantly, followed by D-DBTA as described above to obtain a (+)-sibutramine D-DBTA salt of> 99.3% ee. The sibutramine enantiomers were characterized by ¹ H and ¹³ C NMR: M ⁺ = 279 HPLC. In addition, the properties of the material were confirmed by HPLC and chiral HPLC.

5.2. Example 2: Preparation of Sibutramine from Metabolites

Racemic and optically pure sibutramine can also be made by methylation of desmethylsibutramine or demethylation of didesmethylcibutramine under suitable reaction conditions. An example of this method is shown in Scheme I.

Scheme I

5.3. Example 3: Desmethylsibutramine Preparation from Sibutramine

(-)-Sibutramine (1.25 g) was dissolved in toluene (90 mL) and diethylazodicarboxylate ("DEAD") was added (0.8 g, 1.1 eq). The reaction mixture was heated at 50 ° C. for 6 hours and 0.8 g DEAD was added. The reaction was heated at 50 ° C. for a further 6 hours, cooled to room temperature and toluene was removed under vacuum. The residue was suspended in 45 mL ethanol and 45 mL saturated aqueous NH ₄ Cl. The reaction mixture was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and concentrated to remove ethanol. Aqueous NaHCO ₃ was added until the concentrate was basic. The basic concentrate was extracted with dichloromethane (3 x 50 mL). The extracts were combined, dried over sodium sulfate, filtered and concentrated to afford the crude product. Flash column chromatography (SiO ₂ ) (ethylacetate / TEA 99: 1) produced 0.43 g product. Its characteristics were confirmed by ¹ H and ¹³ C NMR, M + = 266, optical rotation [α] = -10.6, c = 3.3, (CHCl ₃ ). Other enantiomers and racemates were made similar to the above, with the isomer being the (-)-isomer.

Synthesis of Desmethyl sibutramine Isomer

(-)-Desmethyl sibutramine solution (0.78 g) dissolved in ethyl acetate (5 mL) at 0 ° C was added to HCl / diethyl ether (1 M, 5 mL). The reaction mixture was stirred for 1 hour and the solids were collected by filtration. Thereafter, the solid was dried to obtain 0.68 g white solid. The product was characterized by ¹ H and ¹³ C NMR DMSO-d ₆ ), and the chemical purity of> 99% was determined by HPLC. [α] = − 5 ° (c = 0.5, H ₂ O). Racemates and other enantiomers were prepared and characterized in the same manner.

5.4. Example 4: (R / S) -desmethylsibutramine

Another method for preparing racemic desmethyl sibutramine ((R / S) -DMS) is shown in Scheme II and described in detail below.

Scheme II

Preparation of 1- (4-chlorophenyl) -1-cyclobutyl carboxaldehyde

According to Scheme II, diisobutylaluminum chloride (DIBAL-H) (87 mL, 1M / THF, 87.0 mmol) was maintained at -20 ° C. in 1- (4-chlorophenyl) cyclobutanecarbonitrile (CCBC; 10 g , 52.1 mmol). The reaction mixture was stirred at 0 ° C. for 4-5 hours, then poured into 10% aqueous citric acid solution and diluted with 200 mL MTBE. The mixture was stirred at rt for 3-4 h. The aqueous layer was washed with MTBE (1 × 50 mL) and the combined organic layers were dried over MgSO ₄ and concentrated to give 9 g (89%) of the aldehyde in oil. ¹ H NMR (CDCl ₃ ) δ9.52 (s, 1H), 7.35-7.06 (m, 4H), 2.77-2.68 (m, 2H), 2.43-2.32 9m, 2H), 2.06-1.89 (m, 2H) . ¹³ C NMR δ 198.9, 139.4, 132.9, 128.9, 127.8, 57.1, 28.3, 15.8.

Preparation of 1- (4-chlorophenyl) -1-cyclobutyl N-methylcarbimine

A mixture of 1- (4-chlorophenyl) -1-cyclobutyl carboxaldehyde (3 g, 15.4 mmol) and methylamine (12 mL, 40% water soluble w / w, 154 mmol) was stirred at room temperature for 18-40 hours. It was. The reaction mixture was extracted with MTBE (2 x 50 mL). The combined organic layer was dried over K ₂ CO ₃ and concentrated to yield 2.5 g (78%) of this imine in oily form. ¹ H NMR (CDCl ₃ ) δ 7.65 (m, 1H), 7.33-7.11 (m, 4H), 3.34 (s, 3H), 2.69-2.44 (m, 2H), 2.44-2.34 (m, 2H), 2.09 -1.84 (m, 2 H); ¹³ C NMR δ 168.0, 144.0, 131.8, 128.4, 127.4, 50.6, 47.6, 30.6, 15.8.

1- (4-chlorophenyl) -1-cyclobutyl-N-methyl-2- (2-methylpropyl) cyclobutanamethamine

BF ₃ -OEt ₂ (0.34 g, 2.4 mmol) was added to a 1- (4-chlorophenyl) -1-cyclobutyl N-methylcarbimine (0.5 g, 2.4 mmol) solution cooled to 0 ° C. The mixture was stirred for 1 hour and cooled to -78 ° C. At this temperature, isobutyl magnesium bromide (2.5 mL, 2M / ether, 5 mmol) was added to make a mixture, which was stirred at −78 ° C. for 2 hours, then warmed to room temperature and stirred overnight. The reaction was cooled with saturated NaHCO ₃ solution (10 mL) and diluted with MTBE (15 mL). The organic layer was dried over MgSO _4, concentrated and purified by silica gel chromatography (eluted with 1% NEt ₃ in ethyl acetate) to give 380 mg of the amine in oil state. ¹ H NMR (CDCl ₃ ) δ 7.35-7.19 (m, 4H), 2.65-2.74 (m, 1H), 2.57 (s, 3H), 2.20-2.56 (m, 5H), 1.60-2.00 (m, 3H) , 1.20-1.00 (m, 2H), 0.95-0.90 (m, 6H), 0.67-0.60 (m, 1H), ¹³ C NMR δ 144.7, 131.3, 129.1, 127.4, 65.5, 51.7, 41.4, 37.4, 33.7, 32.3, 25.4, 24.0, 22.0, 16.3.

5.5. Example 5: (R / S) -desmethylsibutramineHCl

A method for preparing racemic desmethyl sibutramine hydrochloride ((R / S) -DMS-HCl) is shown in Scheme III.

Scheme III

According to Scheme III, CCBC (50.0 g, 261 mmol) solution in toluene (150 mL) and toluene (45 mL) was dissolved in isobutyl magnesium bromide in THF (392 mL, 1M in THF, 392 mmol). Added. The resulting mixture was distilled until the internal temperature reached 105-110 ° C. and refluxed at this temperature for 2-4 hours. The reaction mixture was then cooled to 0 ° C. and cooled with methanol (295 mL). NaBH ₄ (11 g, 339 mmol) was added in portions to the reaction mixture at 0 ° C. for 15 minutes. After stirring for 15 minutes, the reaction mixture was transferred to a 2N aqueous HCl solution (365 mL). The organic phase was distilled until the internal temperature reached 105 ° C. and then cooled to room temperature. Formic acid (24 g, 522 mmol) is then added to the reaction mixture, after which the reaction mixture is heated under reflux (92-96 ° C.) for 6-8 hours, after which the reaction is carried out until the internal temperature reaches 108 ° C. The mixture was distilled off. The mixture was then cooled to 10 ° C. and BH ₃ -THF (653 mL, 1.0 M, 653 mmol) was added. The resulting mixture was heated at reflux (69 ° C.) for 15 h. The mixture was then cooled to 5 ° C., combined with methanol (105 mL) and refluxed once more for 45 minutes. The reaction mixture was distilled until the internal temperature reached 116 ° C. and then cooled to 25 ° C. Thereafter, hydrochloric acid dissolved in MTBE (373 g, 18 wt% HCl, 1840 mmol) was added to the mixture to form a white slurry, which was refluxed for 1 hour and filtered to give 62.3 g (79.0%) of (R / S). -DMS-HCl was obtained. NMR (CDCl ₃ ): ¹ H (d), 0.85-1.1 (m, 6H), 1.24-1.5 (b, 2H), 1.65-2.14 (b, 4H), 2-2.5 (b, 4H), 2.5- 2.7 (m, 2H), 3.4-3.6 (b, 1H), 7.3-7.5 (m, 4H), 9.0-9.5 (b, 2H). ¹³ C (d): 15.5, 21.4, 23.5, 24.7, 31.4, 32.4, 33.2, 35.9, 49.1, 64.2, 128.5, 129.4, 133.0, 141.6.

5.6. Example 6: (R) -Desmethyl sibutramine-HCl

The method for preparing (R) -desmethylsibutramine hydrochloride ((R) -DMS-HCl) is shown in Scheme IV and described in detail below.

[Scheme] IV ]

Preparation of (R) -mandelate salt of (R) -DMS

(R / S) -Desmethyl sibutramine-HCl (( R / S ) -DMS-HCl) (60 g) was added to ethyl acetate (300 mL), and the resulting mixture was cooled to 0 deg. Thereafter, water-soluble NaOH (1.5 N, 300 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 30 minutes. The organic phase was separated, washed with water (150 mL) and concentrated. Then (R) -mandelic acid (30.3 g), ethyl acetate (510 mL) and heptane (204 mL) were added to the concentrated organic phase. The product mixture was then heated to reflux for 1 hour and then cooled to 20-23 ° C. The resulting slurry was filtered to give 36.4 g (43.8%) of (R) -desmethylsibutramine- ( R ) -mandelate ((R) -DMS- ( R ) -MA; 95.5% ee).

( R ) -DMS- ( R ) -Increase in MA

(R) mixture of -DMS- (R) -MA (30 g , 0.072 mmol), ethyl acetate (230 ㎖), heptane (230 ㎖) was heated at reflux for 1 hour. The product was cooled to 20-23 ° C., filtered and dried to give 29.6 g (98%) of ( R ) -DMS- ( R ) -MA (99.9% ee).

( R ) -DMS HCl Salt Preparation

(R) mixture of -DMS- (R) -MA (50 g , 0.12 mol), NaOH (100㎖, 3.0N), toluene (500 ㎖) was stirred for 30 minutes. The organic phase was washed with water (200 mL), concentrated to 300 mL and cooled to room temperature. To the mixture was slowly added HCl / MTBE (100 mL, 14%, 0.34 mol) to make ( R ) -DMS-HCl. After stirring for 30 minutes, the slurry was filtered and the resulting wet mass was washed twice with MTBE to give 34.5 g (95.5%) of ( R ) -DMS-HCl (99.9% ee; 99.9% purity in NMR). . NMR (CDCl ₃ ): ¹ H (δ), 0.85-1.1 (m, 6H), 1.24-1.5 (b, 2H), 1.65-2.14 (b, 4H), 2.2-2.5 (b, 4H), 2.5- 2.7 (m, 2H), 3.4-3.6 (b, 1H), 7.3-7.5 (m, 4H), 9.0-9.5 (b, 2H), ¹³ C (δ): 15.5, 21.4, 23.5, 24.7, 31.4, 32.4, 33.2, 35.9, 49.1, 64.2, 128.5, 129.4, 133.0, 141.6.

5.7. Example 7: (S) -Desmethyl sibutramine-HCl

The method for preparing (S) -desmethylsibutramine hydrochloride ((S) -DMS-HCl) is shown in Scheme V and described in detail below.

Scheme V

(S) -Mandelate Salt Preparation of (S) -DMS

According to Scheme V, a mixture of (R / S) -DMS-HCl (5.0 g), NaOH (1.5N, 20 mL), ethyl acetate (50 mL) was stirred for 30 minutes. The organic phase was washed with water (20 mL) and concentrated to make desmethylsibutramine freebase (4.2 g, 96%).

Desmethyl sibutramine free base (1.1 g, 4.1 mmol) was combined with (S) -mandelic acid (0.62 g, 4.1 mmol), ethyl acetate (11 mL), heptane (4.4 mL). The resulting mixture was heated to reflux for 30 minutes and cooled to 20-23 ° C. The resulting slurry was filtered to obtain 0.76 g of (S) -desmethyl sibutramine (S) -mandelate salt ((S) -DMS- (S) -MA) (96% ee).

( R ) -DMS- ( R ) -Increase in MA

A mixture of (S) -desmethylsibutramine. (S) -mandelate (0.76 g), ethyl acetate (5 mL) and heptane (5 mL) was heated to reflux for 1 hour. After cooling to 20-23 ° C., the product was filtered and dried to give 0.72 g (95%) of (S) -DMS- (S) -MA (99.9% ee).

(S) -DMS- ( R Recovery of (S) -mandelate salt of (S) -DMS from mother liquor of) -MA

The ( S ) -DMS- ( R ) -MA solution (67% ee mother liquor) dissolved in ethyl acetate-heptane was filled with NaOH (3N, 400 mL) and the reaction mixture was stirred for 30 minutes. The organic phase was washed with water and concentrated. The resulting residue (130 g, 0.49 mol, 67% ee) was charged with ( S ) -mandelic acid (28.5 g, 0.49 mol), ethyl acetate (1400 mL), heptane (580 mL). The mixture was heated at reflux for 1 hour and then slowly cooled to room temperature. The resulting slurry was filtered and dried to give 147 g (86% (S) -isomer) of ( S ) -DMS- ( S ) -MA (99.9% ee).

( S ) -DMS HCl Salt Preparation

( S ) -Desmethyl sibutramine- ( S ) -mandelate (20 g, 0.048 mol) was added to a mixture of NaOH (60 mL, 3.0 N) and toluene (200 mL). The mixture was stirred for 30 minutes and the organic phase was washed with water (100 mL), concentrated to 100 mL and cooled to room temperature. Thereafter, hydrochloric acid dissolved in MTBE (40 mL, 14%, 0.13 mol) was slowly added to the reaction to make ( S ) -DMS-HCl. After stirring for 30 minutes, the slurry was filtered and the resulting wet mass was washed twice with MTBE and dried to give 14 g (96-7%) of ( S ) -DMS- ( L ) -MA (99.9% ee 99.9% chemical purity). NMR (CDCl ₃ ); ¹ H (δ), 0.84-1.1 (m. 6H), 1.25-1.5 (b, 2H), 1.65-2.15 (b, 4H), 2.2-2.5 (b, 4H), 2.5-2.7 (m, 2H) 3.4-3.6 (b, 1 H), 7.3-7.5 (m, 4 H), 9.0-9.5 (b, 2 H). ¹³ C (δ): 15.5, 21.4, 23.5, 24.7, 31.4, 32.4, 33.2, 35.9, 49.1, 64.2, 128.5, 129.4, 133.0, 141.6.

5.8. Example 8 Desmethylsibutramine Preparation from DidesmethylSibutramine

Racemic and optically pure didesmethyl sibutramine can also be made by demethylation of desmethyl sibutramine under suitable reaction conditions. An example of this method is shown in Scheme VI.

[Scheme Ⅵ]

5.9. Example 9: (R / S)-didesmethylbubtramine

A suitable method for preparing racemic didesmethyl sibutramine free base (( R / S ) -DDMS) is shown in Scheme VII and described in detail below.

Scheme VII

According to Scheme VII, a 1 L three necked round bottom flask was filled with magnesium isobutyl bromide (200 mL, 2.0 M / dietherether) and toluene (159 mL), and the resulting mixture was distilled off to remove most ether. After the mixture was cooled to 20 ° C., CCBC (50.0 g) dissolved in toluene (45 mL) was added and the resulting mixture was refluxed for 2-4 hours. The reaction mixture was cooled to 0 ° C., to which methanol (300 mL) was added, followed by the slow addition of NaBH ₄ (11 g). The resulting mixture was stirred at 0-10 ° C. for 15 minutes. Thereafter, the reaction mixture was slowly added to an aqueous HCl solution (365 mL, 2N) kept at 0 ° C., and the resultant mixture was warmed to room temperature with continuous stirring. After separation of the organic phase, the aqueous phase was washed with water (200 mL). The combined organic phase was washed with water (200 mL) and concentrated to give ( R / S ) -DDMS (55 g, 85%). NMR (CDCl ₃ ): ¹ H (δ), 0.6-0.8 (m, 1H), 0.8-1.0 (m, 6H), 1.1-1.3 (m, 1H), 1.6-2.6 (m, 7H), 3.0- 3.3 (m, 1 H), 7.0-7.6 (m, 4 H). ¹³ C (δ): 15.4, 21.5, 24.3, 24.7, 31.5, 31.9, 41.1, 50.73, 56.3, 127.7, 129, 131.6, 144.2.

5.10. Example 10: ( R / S )-Didesmethyl sibutramine D ) -Tartrate

The process for preparing racemic didesmethyl sibutramine ( D ) -tartrate (( R / S ) -DDMS- ( D ) -TA) is shown in Scheme VIII. Racemic didesmethyl sibutramine ( L ) -tartrate ((R / S) -DDMS- ( L ) -TA) can be made in a similar manner.

Scheme VII

According to Scheme VIII, the mixture of racemic didesmethyl sibutramine (15.3 g) and toluene (160 mL) was heated to 70-80 ° C. and dissolved in water (20 mL) and acetone (10 mL) (D) -tartrate (9.1 g) was added slowly. The resulting mixture was refluxed for 30 minutes, after which water and acetone were distilled off. The resulting mixture was cooled to room temperature to form a slurry, which was then filtered. The resulting wet mass was washed twice with MTBE (20 mL × 2) and dried to give ( R / S ) -DDMS- ( D ) -TA (22.5 g, 98%). NMR (DMSO); ¹ H (δ), 0.6-0.92 (m, 6H), 0.92-1.1 (m, 1H), 1.1-1.3 (m, 1H), 1.5-1.8 (m, 2H), 1.8-2.1 (m, 1H, 2.1-2.4 (m, 3H), 2.4-2.6 (m, 1H), 3.4-3.6- (m, 1H), 3.9-4.2, (s, 2H), 6.4-7.2 (b, 6H, OH, COOH and NH ₂ ), 7.3-7.6 (m, 4H), ¹³ C (δ): 15.5, 2.1, 23.3, 23.7,31.5, 31.8, 37.7, 39.7, 54.5, 72.1, 128 129.7, 131.3, 142.2, 174.6.

5.11. Example 11: ( R )-Didesmethyl sibutramine (D) -tartrate

Separation of didesmethyl sibutramine freebase

The method for separating ( R )-didesmethyl sibutramine (D) -tartrate ( R ) -DDMS- ( D ) -TA) from racemic didesmethyl sibutramine free base is shown in Scheme IXA and described in detail below. .

[Scheme VIIA]

According to Scheme IXA, ( R / S )-didesmethyl sibutramine (20.3 g), acetone / water / methanol (350 mL, 1: 0.13: 0.7, v: v: v), ( D ) -tartrate (12.1 g ) Was added to a 500 ml three neck round flask. The reaction mixture was heated at reflux for 30 minutes and then cooled to 45 ° C. Then, ( R ) -DDMS- ( D ) -TA (10 mg; 99.6% ee) was slightly added to the reaction mixture and stirred at 40-45 ° C. for 30 minutes. The mixture was then cooled to room temperature and stirred for 1 hour. The resulting slurry was then filtered to form a wet mass which was washed with cold acetone / water and dried to give 10.3 g (33%) of ( R ) -DDMS- ( D ) -TA (90% ee).

Separation of (R / S)-didesmethyl sibutramine- (D) -tartrate

The method for separating ( R )-didesmethyl sibutramine (D) -tartrate ( R ) -DDMS- ( D ) -TA) from racemic didesmethyl sibutramine (D) -tartrate is shown in Scheme IXB, Describe in detail.

[Scheme VIIB]

According to Scheme IXB, ( R / S )-didesmethyl sibutramine · (D) -TA (5.0 g) dissolved in acetone (50 mL), water (6.7 mL) and methanol (3.3 mL) was refluxed for 30 minutes. . The reaction mixture was then cooled to room temperature and the resulting slurry was filtered to form a wet mass which was washed with cold acetone and dried to give ( R ) -DDMS- ( D ) -TA (1.4 g, 28%; 92 % ee) was obtained.

( R Increase of (D) -Tartrate in) -DDMS

A mixture of ( R ) -DDMS- ( D ) -TA (25 g, 92% ee) and acetonitrile / water / ethanol (300 mL: 65 mL: 30 mL) was refluxed for 1 hour. The mixture was then cooled to room temperature to form a slurry, which was filtered and dried to give ( R ) -DDMS- ( D ) -TA (18 g, 71.3%; 99.7% ee; 99.91% chemical purity). NMR (DMSO-d ₆ ): ¹ H (δ), 0.7-0.9 (m, 6H), 0.9-1.05 (t, 1H), 1.1-1.24 (b, 1H), 1.5-1.8 (b, 2H), 1.8-2.02 (b, 1H), 2.1-2.4 (3,3H), 2.4-2.6 (b, 1H), 3.5 (m, 1H), 4.0 (s, 2H), 7.1-7.6 (m, 4H, with 6H from NH ₂ , OH and COOH). ¹³ C (δ): 15.4, 21.5, 22.0, 22.2, 32.0, 32.2, 38.4, 49.0, 54.0, 72.8, 128.8, 130.0, 132.0 143.0, 175.5.

5.12. Example  12: (S)- Didesmethylcibutramine (L)- Stannate

The separation of ( S )-didesmethyl sibutramine (L) -tartrate (( S ) -DDMS- ( L ) -TA) from racemic didesmethyl sibutramine freebase is shown in Scheme X and described in detail below. do.

Scheme X

( S ) -DDMS (L) -Tartrate Preparation

(R / S) didesmethyl sibutramine (20.5 g), acetone / water / methanol (350 mL, 1: 0.13: 0.7, v: v: v), ( L ) -tartrate (12.2 g) is 500 mL 3 It was added to a round bottom flask. The mixture was heated at reflux for 30 minutes and then cooled to 45 ° C. Then, (S) -DDMS- (L) -TA (10 mg; 99.7% ee) was slightly added to the reaction mixture and stirred at 40-45 ° C. for 30 minutes. The mixture was then cooled to room temperature and stirred for 1 hour. The resulting slurry was then filtered to form a wet mass which was washed with cold acetone / water and dried to give 10.8 g (33.4%) of (S) -DDMS- ( D ) -TA (89.7% ee).

* Preparation of (L) -tartrate of ( S ) -DDMS from ( R ) -DDMS- ( D ) -TA mother liquor

The DDMS solution (( R ) -DDMS- ( D ) -TA) mother solution in acetone / water / methanol was concentrated to remove acetone and methanol. The residue was treated with aqueous NaOH (3N, 150 mL) and extracted with ethyl acetate. The organic phase was washed with water (100 mL) and concentrated to give didesmethyl sibutramine freebase (45 g, 0.18 mol, 36% ee ( S ) -isomer). The free amine was charged with ( L ) -tartrate (53.6 g, 0.35 mol), acetone (600 mL), water (80 mL), methanol (40 mL). The mixture was heated at reflux for 1 h and then cooled to room temperature. The resulting slurry is filtered to create a wet mass, after cooling and cleaning it of acetone / water 2 26.7 g - (S) -DDMS- ( L) -TA (96% of (56% (S) di-desmethyl sibutramine) ee).

Increase in (S) -DDMS ・ (L) -TA

The ( S ) -DDMS- ( L )-(26.7 g) mixture dissolved in acetonitrile / water (475 mL, 1: 0.2, v: v) was refluxed for 1 hour and then cooled to room temperature. The resulting slurry was filtered and dried to afford 17.4 g (65%) of ( S ) -DDMS- ( L ) -TA (99.9% ee; 99.94% chemical purity). NMR (DMSO-d6): ¹ H (δ), 0.7-0.9 (m, 6H), 0.9-1.05 (m, 1H), 1.1-1.3) (b, 1H), 1.52-1.8 (b, 2H), 1.84-2.05 (b, 1H), 2.15-2.4 (b, 3H), 2.4-2.6 (b, 1H), 3.65-3.58 (m, 1H), 4.0 (s, 2H), 6.7-7.3 (b, 6H from NH ₂ , OH and COOH) 7.1-7.6 (m, 4H). ¹³ C (δ): 15.4, 21.5, 22.0, 22.2, 32.0, 32.2, 38.4, 49.0, 54.0, 72.8, 128.8, 130.0, 132.0, 143.0, 175.5.

5.13. Example 13: Effectiveness and Specificity Measurement

Pharmacological studies are performed to determine the racemic mixture of sibutramine, its enantiomers, metabolites of sibutramine, their relative efficacy, comparative efficacy, binding affinity, and toxicity. The relative specificity profile of monoamine reuptake inhibition was determined from inhibition of norepinephrine (NE) reuptake and dopamine (DA) and serotonin (5-HT) reuptake of the compound in brain tissue.

* High-affinity acceptance of ³ H-radioactive monoamines is described by Kual et al. , Using the method disclosed in Life Sciences 34 (26) : 2567-2575, 1984, Baldessarini et al., Life Sciences 39 : 1765-1777, 1986, using the methods disclosed in 1986 (1765-1777, 1986). Investigate in the conjugate preparations made in (5HT and NE). Tissues were finely cut and weighed on ice. After homogenization by hand in a Teflon-on-glass homogenizer [stroke 14 times in 10-35 volumes of ice-cooled 0.32 M isotonic sugar containing nialamide (34 μM)], the tissue was allowed to dry at 900 xg for 10 minutes. Centrifuge during; The resulting upper "solution" contains a synaptosome that is used without further experimentation. Each assay tube contains 50 μl of cerebral homogenate, radiolabeled ³ H-monoamine, test compound (e.g., pure sibutramine enantiomer, racemate, appropriate standard) in freshly prepared 0.5 ml final volume of physiological buffer solution. It contains. Tissues are preincubated for 15 minutes at 37 ° C. before analysis. The tube is left on ice until the start of incubation, initiating the incubation by adding ³ H-monoamine and bringing the final concentration to 0.1 μM. The tube is incubated with ³ H-DA (26 Ci / mmol) for 10 minutes at 37 ° C. with ³ H-5HT (20 Ci / mmol) and ³ H-NE (20 Ci / mmol) for 20 minutes. The specific activity of the radiomonamine depends on the material, but is not very important. The reaction was terminated by dipping in ice and diluting with 3 ml ice chilled isotonic solution containing 20 mM TRIS buffer (pH 7.0). These solutions were filtered through a cellulose ester microfilter and then washed twice with 3 ml of the same buffer. The filter then calculates the ³ H-radioactivity on 3.5 ml Polyfluor phase at 50% efficacy against tritium. Blanks [incubated at 0 ° C., or with known specific receptor inhibitors DA (GRB-12909, 10 μM), 5HT- (zimelidine 10 μM) or NE (decimepramine 10 μM) were performed without tissue. Indistinguishable from analysis, overall CPM averages 2-3%.

Comparing the amount of ³ H-radioactive activity remaining in the filter, the pure enantiomer of sibutramine and the racemic mixture (also DA, 5-HT, NE re-receptive inhibitors) block the re-receipt of monoamines in these tissues. You can compare the ability of This information is useful for evaluating the relative effectiveness and efficacy of the compounds of the present invention (eg, dopamine reuptake inhibitors such as racemic or optically pure sibutramine metabolites and 5-HT ₃ antagonists).

Acute toxicity of the compounds of the present invention is determined by experiments in which mice are dosed with progressively higher doses (mg / kg) of the pure isomers or racemates. The lethal dose administered orally to kill 50% of the experimental animals is defined as LD ₅₀ . The relative toxicity of the composition is determined by comparing the LD ₅₀ values for the enantiomers and racemates.

5.14. Example 14 Binding Affinity

Racemic and optically pure sibutramine ((±)-, (+)-, (-)-sibutramine), desmethylsibutramine ((±)-, (+)-, (-)-desMe), didesmethyl sibutramine The binding affinity of ((±)-, (+)-, (-)-didesMe) was associated with non-selective muscarinic receptors and serotonin (5-HT) receptor sites and adult recombinant norepinephrine (NE) receptor sites in the rat cerebral cortex. , And measured at β ₃ receptor of rat adipocytes. Compounds were tested two times at 10 μm, and two additional experiments were conducted at ten different concentrations to obtain complete competition curves when ≧ 50% specific binding inhibition was observed. IC ₅₀ values (required concentrations that inhibit specific binding by 50%) were determined by curve nonlinear regression, with the results as follows.

No compound showed more than 15% inhibition at the β ₃ -receptor, and the affinity for the muscarinic site was weak compared to atropine. In addition, the binding of NE with the 5-HT receiving site was much less than that of the reference.

The data, made as described above in Example 13, shows that (+)-desmethylsibutramine and (+)-didesmethylcibutramine are potent inhibitors of NE and 5HT uptake but show little activity on muscarinic receptors. Shows.

5.15. Example 15 Oral Compositions

Lactose-free light gelatin capsule dosage forms consisting of sibutramine metabolites can be prepared using the following ingredients.

The racemic or optically pure sibutramine metabolite is sieved and mixed with excipients. The mixture is filled into appropriately sized two-piece light gelatine capsules using suitable machinery and methods known in the art ( Remington's Pharmaceutical Sciences , 16th or 18th Editions). Other doses can be made by modifying the fill weight and resizing the capsule if necessary. Any stable lactose-free light gelatin capsule composition can be made.

Compressed tablet formulations of sibutramine metabolites can be made using the following ingredients.

ingredient 5mg Capsules 10mg capsule 20mg capsule Racemic or optically pure sibutramine metabolite 5.0 10.0 20.0 Microcrystalline cellulose 900 90.0 90.0 Pre-gelatinized starch 100.3 97.8 82.8 Croscarmellose 7.0 7.0 7.0 Magnesium stearate 0.2 0.2 0.2

The racemic or optically pure sibutramine metabolite is sieved and mixed with non-lactose excipients until a uniform mixture is formed. The dried mixture is sieved and mixed with magnesium stearate. The resulting powder mixture is pressed into the desired shape and size. Tablets of different strength can be made by modifying the ratio of active ingredient to excipient or by modifying the tablet weight.

Embodiments of the invention described above are intended to illustrate, and those skilled in the art can readily recognize a number of equivalents to the specific processes described above using routine experimentation. Such equivalents fall within the scope of the present invention and are included in the appended claims.

It suggests how to treat and prevent diseases and abnormalities including erectile dysfunction, mood disorder, weight gain or obesity, brain function disorder, pain, obsessive compulsive disorder, drug abuse, chronic disease, anxiety, eating disorder, migraine, incontinence.

Claims (19)

delete (-)-Didesmethyl sibutramine or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, wherein at least 90% of the total weight of total didesmethyl sibutramine is (-)-didesmethyl sibutramine A pharmaceutical composition for treating Parkinson's disease, characterized in that. delete The pharmaceutical composition according to claim 2, wherein the amount of (-)-didesmethyl sibutramine is 0.1 mg to 60 mg. The pharmaceutical composition according to claim 4, wherein the amount of (-)-didesmethyl sibutramine is 2 mg to 30 mg. The pharmaceutical composition according to claim 5, wherein the amount of (-)-didesmethyl sibutramine is 5 mg to 15 mg. The pharmaceutical composition according to claim 2, which is administered orally, mucosa, rectum, extragranular, transdermal or subcutaneous. 8. A pharmaceutical composition according to claim 7, which is administered orally. The pharmaceutical composition of claim 2 comprising a pharmaceutically acceptable excipient. The pharmaceutical composition for treating Parkinson's disease according to claim 2, wherein at least 95% of the total weight of didesmethyl sibutramine is (-)-didesmethyl sibutramine. 11. The pharmaceutical composition for treating Parkinson's disease according to claim 10, wherein at least 99% of the total weight of didesmethyl sibutramine is (-)-didesmethyl sibutramine. delete delete delete delete delete delete delete delete